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PNAS 105 (43): 16602-16607

Copyright © 2008 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

A bacterial control circuit integrates polar localization and proteolysis of key regulatory proteins with a phospho-signaling cascade

Antonio A. Iniesta Lucy Shapiro*

Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305

Contributed by Lucy Shapiro, September 5, 2008

Received for publication August 14, 2008.

Abstract: Dynamic protein localization is an integral component of the regulatory circuit that drives the Caulobacter cell cycle. The ClpXP protease is localized to the Caulobacter cell pole, where it catalyzes the degradation of the CtrA master regulator at specific times in the cell cycle. Clearance of active CtrA at the G1/S transition allows the initiation of DNA replication and cell-cycle progression. The polar localization of ClpXP is dependent on the polar positioning of the CpdR single-domain response regulator. Only the unphosphorylated form of CpdR localizes and activates ClpXP. We demonstrate that another single domain response regulator, DivK, promotes the polar accumulation of unphosphorylated CpdR and that CpdR is subsequently degraded at the cell pole by the localized ClpXP protease. Thus, CpdR function is regulated by a feedback loop that incorporates its differential phosphorylation, the transient polar localization and activity of the ClpXP protease, and the clearance of the CpdR by polar ClpXP that, in turn, releases ClpXP from the pole relieving the degradation of CtrA. CtrA~P then accumulates and activates the transcription of cpdR, completing the regulatory loop, establishing an integrated network that controls a robust cell-cycle transition.

Key Words: Caulobacter • ClpXP • feedback • cell-cycle • CtrA

Author contributions: A.A.I. designed research; A.A.I. performed research; A.A.I. analyzed data; and A.A.I. and L.S. wrote the paper.

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/cgi/content/full/0808807105/DCSupplemental.

*To whom correspondence should be addressed. E-mail: shapiro{at}stanford.edu

© 2008 by The National Academy of Sciences of the USA

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